The observation of glucocorticoid modulation during tuberculosis infection has been known for many years, however the relationship between glucocorticoid immunomodulation and destructive pathological and granulomatous responses to mycobacterial antigens remains poorly understood. Indeed, relative amounts of both systemic and tissue specific cortisol may be crucial in susceptibility to tuberculosis, and therefore play a defining role in ensuing pathology. C57BL/6 mice demonstrate a rapid decrease in serum cortisol levels during initiation of granulomatous response during acute experimental infection with virulent Mycobacterium tuberculosis. Investigators have actively pursued agents that mimic immunopathology associated with tuberculosis. One such agent; the natural mycobacterial glycolipid trehalose 3,6'dimycolate (TDM) has been researched extensively as a mediator of biological events and granulomatous responses during disease. We have further identified mycobacterial TDM as able to influence systemic serum cortisol levels. This is the first observation of mediation of a systemic glucocorticoid to a mycobacterial glycolipid, and warrants further investigation. Our preliminary findings indicate a need to explore the influence of cortisol on initial events involved in the immunoregulation and immunopathology due to mycobacterial glycolipid TDM. The goal of this application is therefore to examine the relationship between immune- responses induced by mycobacterial glycolipid and associated concurrent imbalances in both serum and tissue glucocorticoids (cortisol) during development of the pulmonary granulomatous response. We request that this proposal be considered for R21 funding directed towards exploratory research into applications of physioneuroimmunology towards understanding the basis of immunoregulated disease pathology during tuberculosis infection.